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Synthesis and application of antineoplastic 2-amino-3-cyano pyridine

A technology for anti-tumor drugs and compounds, applied in the field of medicine, can solve problems such as poor selectivity, toxic and side effects, and achieve the effects of rapid reaction, high selectivity and high atom economy

Inactive Publication Date: 2013-02-13
CHINA PHARM UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the existing tumor drugs have problems such as poor selectivity, toxic side effects, and drug resistance.

Method used

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  • Synthesis and application of antineoplastic 2-amino-3-cyano pyridine
  • Synthesis and application of antineoplastic 2-amino-3-cyano pyridine
  • Synthesis and application of antineoplastic 2-amino-3-cyano pyridine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029]

[0030] 4-(4-Hydroxyphenyl)-6-p-fluorophenyl-2-amino-3-cyanopyridine (a) W21

[0031] Dissolve p-hydroxybenzaldehyde (2mmol), 4-fluoroacetophenone (2mmol), and malononitrile (2mmol) in 1,4-dioxane, then add ammonium acetate (4mmol), microwave (300W) Auxiliary heating at 120°C for 20 minutes. Ice water was added to the reaction mixture to precipitate the product, and then recrystallized to obtain the product with a yield of 82%. IR(KBr)v / cm -1 : 3513, 3411, 3359, 2211, 1610, 1595, 1575, 1551, 1512, 1370, 1283, 1217, 1163, 823; 1 H NMR (300MHz, DMSO-d 6 )δ / ppm: 9.91(s, 1H, OH), 8.15-8.21(m, 2H, ArH), 7.55(d, 2H, ArH, J=8.7Hz), 7.31(t, 2H, ArH, J=9.0 Hz), 7.22(s, 1H, H5), 6.85-6.96(m, 4H, ArH, NH 2 ); 13 C NMR (75.5MHz, DMSO-d 6 )δ / ppm: 160.9, 158.9, 157.2, 154.8, 134.2, 129.8, 129.5, 129.4, 127.4, 117.3, 115.6, 115.5, 108.7, 86.2; MS (ESI) mz: 306.0 [M+H] + ;Anal.Calcd for C 18 h 12 FN 3 O: C, 70.81; H, 3.96; N, 13.76; found: C, 70.72; H, 3.90; N, 13.72.

Embodiment 2

[0033]

[0034] 4-(4-Hydroxyphenyl)-5-methyl-6-p-chlorophenyl-2-amino-3-cyanopyridine (b) W23

[0035] Dissolve p-hydroxybenzaldehyde (2mmol), 4-chloropropiophenone (2mmol), and malononitrile (2mmol) in 1,4-dioxane, then add ammonium acetate (4mmol), and microwave (300W) assisted Heat at 120°C for 20 minutes. Ice water was added to the reaction mixture to precipitate the product, and then recrystallized to obtain the product with a yield of 72%. IR(KBr)v / cm -1 : 3457, 3360, 3241, 2217, 1634, 1550, 1516, 1249, 1167, 1092, 842; 1 H NMR (300MHz, DMSO-6d) δ / ppm: 9.75(s, 1H, OH), 7.48-7.55(m, 4H, ArH), 7.19(d, 2H, ArH, J=7.5Hz), 6.89(d , 2H, ArH, J=7.5Hz), 6.67 (s, 2H, NH 2 ), 1.85 (s, 3H, CH 3 ); 13C NMR (75.5MHz, DMSO-6d) δ / ppm: 159.8, 158.0, 157.8, 155.4, 133.1, 130.9, 130.7, 129.8, 127.9, 127.2, 117.1, 116.8, 115.3, 89.9, 16.7; MS (ESI) mz: 336.1[M+H] + , 358.1[M+Na] + ;Anal.Calcd for C 19 h 14 CIN 3 O: C, 67.96; H, 4.20; N, 12.51; found: C, 67.85; H, 4.29; N, 12...

Embodiment 3

[0036] Embodiment 3 is related to the pharmacological experiment of (W21) and (W23)

[0037] 1. Evaluation of antitumor activity in vitro

[0038] 1.1 Test substance

[0039] a(W21) is the compound prepared in Example 1 of the present invention, and its Chinese name is 4-(4-hydroxyphenyl)-6-p-fluorophenyl-2-amino-3-cyanopyridine; b(W23) is based on The compound prepared in Invention Example 2 has a Chinese name of 4-(4-hydroxy-3,5-dimethoxyphenyl)-6-phenyl-2-aminonicotinonitrile. The positive drug is doxorubicin, purchased from Sigma.

[0040] 1.2 Tested cell lines

[0041] Human gastric cancer SGC7901, human liver cancer HepG2, human leukemia cell line HKB, human pancreatic cancer cell line KP4, and human lung cancer cell lines NCI-H292 and NCI-H727 were selected.

[0042] 1.3 Experimental method

[0043] Take a bottle of cells in a good state in the exponential growth phase, add 0.25 trypsin to digest the cells, add complete medium to neutralize the trypsin, blow evenly...

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Abstract

The invention provides a novel antineoplastic drug shown in a molecular formula (I). The synthesis method of the drug is simple and convenient, and the drug can be quickly and efficiently synthesized through microwave-assisted one-pot four-component reaction. The synthesis method comprises the following specific steps: dissolving 2 mmol of p-hydroxybenzaldehyde, 2 mmol of 4-fluoroacetophenone or 4-chloropropiophenone and 2 mmol of malononitrile in 1,4-dioxane; then adding 4 mmol of ammonium acetate; performing microwave (300W)-assisted heating to 120 DEG C, and reacting for 20 minutes; and adding ice water into the reaction mixture to precipitate a product, and then recrystallizing to obtain the product, namely 2-amino-3-cyano pyridine. The compound obtained by the invention is a novel antineoplastic drug shown in the molecular formula (I), and has the activity of obviously inhibiting the proliferation of liver cancer, stomach cancer, mammary cancer, pancreatic cancer, brain cancer, lung cancer and ovarian cancer cells.

Description

1. Technical field [0001] The invention provides a novel 2-amino-3-cyanopyridine antitumor drug, a pharmaceutical composition containing the compound and its use as an antitumor agent, belonging to the technical field of medicine. 2. Background technology [0002] Malignant tumors seriously threaten human life and health. About 7 million people die from cancer every year in the world, accounting for about a quarter of the total death toll. Gastric cancer is the most common malignant tumor in my country, and its death rate accounts for the first place among all kinds of malignant tumors. Liver cancer is the second cancer "killer" in my country, and it has jumped to the first in some high-incidence areas of liver cancer, accounting for 45% of liver cancer deaths worldwide. At present, the mortality rate of existing cancer patients exceeds 30%, which has become the second largest factor in the death of Chinese residents. Pancreatic cancer is one of the cancers with the highes...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/84A61K31/4418A61P35/00A61P35/02
Inventor 张评浒杨晓慧郑祖国张陆勇周永红王治民
Owner CHINA PHARM UNIV
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